The endocannabinoids system (ECS) has garnered considerable interest as a potential therapeutic target in various carcinomas and cancer-related conditions alongside neurodegenerative diseases. Cannabinoids are implemented in several physiological processes such as appetite stimulation, energy balance, pain modulation and the control of chemotherapy-induced nausea and vomiting (CINV). However, pharmacokinetics and pharmacodynamics interactions could be perceived in drug combinations, so in this short rentryview we tried to shed light on the potential drug interactions of medicinal cannabis. Hitherto, few data have been provided to the healthcare practitioners about the drug–drug interactions of cannabinoids with other prescription medications. In general, cannabinoids are usually well tolerated, but bidirectional effects may be expected with concomitant administered agents via affected membrane transporters (Glycoprotein p, breast cancer resistance proteins, and multidrug resistance proteins) and metabolizing enzymes (Cytochrome P450 and UDP-glucuronosyltransferases). Caution should be undertaken to closely monitor the responses of cannabis users with certain drugs to guard their safety, especially for the elderly and people with chronic diseases or kidney and liver conditions.
Cannabis-Based Treatment | Study Type/Location/ | n | Dosage/Administration | Efficacy, Tolerability and Notes | References | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Chemotherapy-Induced Nausea and Vomiting (CINV) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
[ | 19 | ] | [54][55] | -Dronabinol [Marinol | ® | ; (-) trans Δ | 9 | -THC) alone or in combination with ondansetron (8–15 mg IV] | -Interventional (Placebo controlled). - | n | = 64. | |||||||||||||||||||||||||||||||||||||||||||||||||
Δ | 9 | -THC, CBD and marijuana inhalation with psychotropic agents -USA. |
-Capsule (2.5–20 mg). |
-Cytochrome P450-Oral. | - | CYP2C9 | and | CYP3A4 | were inhibited by Δ | 9 | -THC. - | CYP2C19 | and | CYP3A4 | were inhibited by CBD. - | CYP1A1 | and | CYP1A2 | were induced by marijuana inhalation. |
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-Both were effective in CINV and well tolerated while dronabinol was more effective. -Combination is not more effective. |
[56][27] | ||||||||||||||||||||||||||||||||||||||
-Dronabinol [Marinol | ® | ; (-) trans Δ | 9 | -THC] | -Interventional (retrospective). -Children with malignancy. |
-Solution administered orally (2.5–5 mg/m | 2 | body surface every 6 h as needed). | -Positive responses were reported for 60% of patients. -Prospective trial would be needed to confirm the dronabinol effect in CINV therapy. |
[28] | ||||||||||||||||||||||||||||||||||||||||||||||||||
Cannabinoids on other drugs | Cytochrome P450 | - | CYP3A4 | inhibitors and stimulators affect the elimination of Δ | 9 | -THC and CBD. |
| [57] | -Nabilone with 5HT | 3 | antagonist | -Interventional (retrospective) - | n | = 110 with median age 14 years with malignancy. | -Oral. | |||||||||||||||||||||||||||||||||||||||||||||
CBD with antiepileptic drugs | Cytochrome P450 or unknown | Clinical studies of DDI | : -Non-significant increase of the clobazam plasma level administered with CBD ( | n | = 13 children) due to potent inhibition of | CYP2C19 | . -Significant change of plasma level of N-desmethylclobazam by CBD co-administration while no significant change in the level of valproate, stiripentol and levetiracetam ( | n | = 24 open label trial). -All patients showed significant changes of the plasma levels of clobazam, N-desmethylclobazam, rufinamide, and topiramate by increasing CBD doses. The mean therapeutic range was exceeded for clobazam and N-desmethylclobazam; the plasma levels of eslicarbazepine and zonisamide were increased in adults only ( | n | = 39 adults and 42 children). |
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-Adverse effect was reported with minor clinical significance. -Poor nausea control in nabilone treated group. |
[51][58][29] | ||||||||||||||||||||||||||||||||||||||||||||||
Cancer Pain | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Synthetic and Phyto-cannabinoids | -Cytochrome P450 -UGTs |
- | CYP1A | catalysed MROD activity was weakly inhibited by MAM-2201, JWH-019, STS-135, and UR-144. - | CYP2C8 | catalysed amodiaquine N-deethylase was strongly inhibited by AM-2201, MAM-2201, and EAM-2201. - | CYP2C9 | catalysed diclofenac hydroxylation and | CYP3A | -catalyzed midazolam 1′-hydroxylation were inhibited by AM-2201 and MAM-2201. - | CYP2C9 | catalysed diclofenac 4′-hydroxylation, | CYP2C19 | -catalyzed [S] -mephenytoin 4′-hydroxylation, and | CYP3A | -catalyzed midazolam 1′ hydroxylation were strongly inhibited by EAM-2201 (time-dependent inhibition). - | CYP2B6 | and | CYP2C9 | were strongly inhibited by THC, CBN and CBD. - | CYP2A6 | was inhibited by THC and CBN (mechanism-based inhibition). - | CYP2D6 | was competitively inhibited by CBD. - | CYP1A1 mRNA | expression was increased by THC in Hepa-1 cells, but EROD activity in CYP1A1 supersomes was inhibited by THC. - | CYP1A1 | , | CYP1A2 | , and | CYP1B1 | were strongly inhibited by CBD (mechanism-based inhibition). - | CYP3A | was inhibited by CBD in human liver microsomes. - | CYP2C19 | -catalyzed [S] -mephenytoin hydroxylation was inhibited by (CBD and THC (Mixed-type inhibition). - | UGT1A9 | - and | UGT2B7 | catalysed ethanol glucuronidation were non-competitively inhibited by CBD, and unlike the inclined ethanol glucuronidation in human liver microsome by CBN (dose-dependent). - | UGT1A3 | catalysed chenodeoxycholic acid 24-acyl glucuronidation was strongly competitively inhibited by AM-2201, MAM-2201, and EAM-2201. - | UGT2B7 | -Sativex | ® | (Δ | 9 | -THC: CBD at a ratio of 27:25 mg/mL) -THC (27 mg/mL) |
-Interventional (Double-Blind, Randomized, Parallel-Group, Placebo-Controlled), | n | = 177. -Phase 3. -UK. |
-Oromucodal spray with maximum Δ | 9 | -THC: CBD (130:120 mg/day) or 130 mg/day Δ | 9 | -THC alone Each actuation is 100 μL. |
-Compared with the placebo, the Sativex treated group showed significant pain relief, unlike the Δ | 9 | -THC which was non-significant. -Reported adverse effects included dizziness, gastrointestinal disorders and confusion. |
[30] |
-Sativex | ® | (Δ | 9 | -THC: CBD at a ratio of 27:25 mg/mL) | -Interventional (single group assignment) -Phase 3. -UK. |
-Oromucodal spray with a maximum 130:120 mg/day of Δ | 9 | -THC: CBD. | -The long-term use is well tolerated without losing pain-relieving effects in terminal cancer-related pain refectory to opioids. -Adverse effects and tolerability were assessed at the RCT withdrawal visit, 7–10 days later, then monthly, and at the withdrawal or completion of the study. |
[31] |
Cannabinoid Based Treatment and Interactions | Affected Transporters and/or Metabolic Enzymes | Experimental Results, Notes and Outcomes | References | |||||||||||||||||||||||||||||||||||
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Cannabis, THC, CBD, CBN with either chemotherapy, abuse drugs or medications | -Membrane transporters ABC superfamily (glycoprotein P; P-gp, Breast cancer-resistance protein; BCRP, and multidrug resistance protein; MRP1, 2, 3 and 4) -Cytochrome P450 (3A, 2D6, 2C9, 1A1, 1A2, 1B1, 2B6 and 2C8) -UDP-glucuronosyltransferases (UGTs) |
- | P-gp, BCRP, and MRP1-4 | transporters expression were dysregulated by cannabinoids, but in higher concentrations than that usually measured in cannabis smokers. - | CYP3A | was competitively inhibited by THC, CBD and CBN, with CBD being the most potent in a concentration compatible with that in usual cannabis inhalation. - | CYP2D6 | was inhibited by THC, CBD and CBN, with CBD being the most potent in a higher concentration than that in usual cannabis consumption. - | CYP2C9 | was inhibited by THC, CBD and CBN, with CBD inhibitory effect being dependent on the used substrates. - | CYP1A1 | , | 1A2 | , | 1B1 | , | 2B6 | , | 2C19 | , | 3A4 | and | 2C8 | were strongly inhibited by CBD. - | UGT1A9 | , and | 2B7 | were inhibited by CBD. - | UGT1A7 | , | 1A8 | , and | 1A9 | were inhibited by CBN. - | UGT2B7 | was activated by CBN. |
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-mediated naloxone 3β-D-glucuronidation was competitively inhibited by AM-2201. | ||||||||||||||||||||||||||||||||||||||
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- Sativex | ||||||||||||||||||||||||||||||||||||||
® | (Δ | 9 | -THC: CBD at a ratio of 27:25 mg/mL) | -Interventional (Double-Blind, Randomized, Parallel-Group, Placebo-Controlled). -Phase 3. -Multicentric. - | n | = 399. | -Oromucodal spray (100 μL per actuation twice daily in the morning and evening with a maximum of 10 sprays for 5 weeks). | -No significant difference was reported in advanced cancer patients with chronic pain (unalleviated with opioids). -Nabiximol is still beneficial to secondary endpoints. -No evidence of abuse or misuse was reported. |
[32] | |||||||||||||||||||||||||||||
-No significant difference was reported in advanced cancer patients with chronic uncontrolled pain. | [33] | |||||||||||||||||||||||||||||||||||||
-Nabiximols (Sativex | ® | ; Δ | 9 | -THC: CBD at a ratio of 27:25 mg/mL) | -Interventional (Double-Blind, Randomized, Parallel-Group, Placebo-Controlled). -Phase 2. -USA. - | n | = 360. | -Oromucodal spray in low (1–4 sprays/day), medium (6–10 sprays/day) and high (11–16 sprays/day) doses. | -Efficacy and safety were reported at low and medium doses against advanced cancer pain. -The adverse effects at high doses. |
[34] | ||||||||||||||||||||||||||||
-Nabiximols (Sativex | ® | , Δ | 9 | -THC: CBD at a ratio of 27:25 mg/mL) | -Interventional (Double-Blind, Placebo-controlled, Crossover Pilot trial). - | n | = 16. | -Sublingual spray (7.5–30 mg/day). | -No significant difference was reported against chemotherapy-induced neuropathy. -Two-fold reduction of the pain in the responder group with adverse effects. |
[35] | ||||||||||||||||||||||||||||
Cannabis cigarettes (3.56% Δ | 9 | -THC) in combination with opiates | -Interventional (open label). | -Pulmonary administration for chronic pain, including cancer patients. | -Declined chronic pain around 27% in patients receiving oxycodone or morphine analgesics. -No serious adverse effects were reported. |
[36] |
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59 |
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This work was partially supported by the Maxwell Family Foundation and Cairo University via the mission's sector at the Ministry of higher education, Cairo, Egypt.